Fatty alcohol esters of hydroxycarboxylic acids

ABSTRACT

Described herein are compositions (e.g., a pharmaceutical composition) and compounds of formula I, methods of making compounds of formula (I) and their use in the treatment and/or prevention of diseases and disorders.

CLAIM OF PRIORITY

This application is a continuation of U.S. Ser. No. 13/823,406, filedSep. 16, 2011, which is a national stage application under 35 U.S.C.§371 of International Application No. PCT/US2011/051960, filed Sep. 16,2011, which claims priority to U.S. Ser. No. 61/383,894, filed Sep. 17,2010, the content of each of which is incorporated by reference in itsentirety.

TECHNICAL FIELD OF THE INVENTION

The invention relates to fatty alcohol esters of hydroxycarboxylicacids, their compositions and methods of use as a sclerosant (e.g., fortreating varicose veins). The invention also relates to methods ofmaking compounds of formula (I) in scalable (e.g., multi-kilogram scale)batches.

BACKGROUND OF THE INVENTION

Sclerotherapy is a treatment that intentionally damages the lining(endothelium) of small veins and is commonly used to treat blood vesselmalformations such as varicose veins and spider veins. By doing this andthen applying pressure the vein walls stick together. The vein can thenno longer fill with blood and so it is obliterated. One commonly usedSclerosant is a fatty alcohol known as polidocanol. Polidocanol is theactive ingredient used in the FDA-approved Asclera®.

To date, sclerotherapy is accomplished by injecting the the malformedveins with a sclerosing solution causing the target vein to shrink, andsubsequently dissolve over a period of time as the body naturallyabsorbs the treated vein. While sclerotherapy is effective, thereremains a need for a less invasive, more versatile sclerosant, i.e., onewhich may be administered in a number of different ways.

SUMMARY OF INVENTION

In one aspect, the present invention is directed to a compound offormula (I):

wherein

-   R¹ is a C₈₋₃₅ alkyl;-   n is an integer from 2 to 35; and-   R² is hydrogen, alkyl, aryl, heteroaryl, heterocyclyl or aralkyl;-   or a pharmaceutically acceptable salt thereof.

In certain embodiments, n is an integer from 2 to 25. In someembodiments, n is an integer from 2 to 15. In some embodiments, n is aninteger from 2 to 10. In some embodiments, n is an integer from 4 to 10.In some embodiments, n is 2. In some embodiments, n is 6. In someembodiments, n is 7. In some embodiments, n is 8. In some embodiments, nis 9. In some embodiments, n is 10. In some embodiments, n is 11. Insome embodiments, n is 12.

In certain embodiments, R¹ is a C₈₋₂₅ alkyl group. In some embodiments,R¹ is a C₈₋₂₀ alkyl group. In some embodiments, R¹ is a C₁₀₋₁₅ alkylgroup. In some embodiments, R¹ is a C₁₂ alkyl group.

In certain embodiments, R² is alkyl (e.g., C₁₋₄ alkyl). In certainembodiments, R² is C₁₋₄ alkyl (e.g., methyl). In certain embodiments, R²is aryl (e.g., phenyl). In some embodiments, R² is aralkyl (e.g.,benzyl).

In certain embodiments, a compound described herein (e.g., a compound offormula (I)) is a racemic mixture (e.g., less than 10% enantiomericexcess of either the R or S stereoisomer). In certain embodiments, acompound described herein (e.g., a compound of formula (I)) is at least10% enantiomeric excess of the R stereoisomer.

In certain embodiments, the compounds described herein (e.g., a compoundof formula (I)) is at least 50% enantiomeric excess of the Rstereoisomer. In some embodiments, the compound described herein (e.g.,a compound of formula (I)) is at least 75% enantiomeric excess of the Rstereoisomer. In some embodiments, the compound described herein (e.g.,a compound of formula (I)) is at least 85% enantiomeric excess of the Rstereoisomer. In some embodiments, the compound described herein (e.g.,a compound of formula (I)) is at least 90% enantiomeric excess of the Rstereoisomer. In some embodiments, the compound described herein (e.g.,a compound of formula (I)) is at least 95% enantiomeric excess of the Rstereoisomer. In some embodiments, the compound described herein (e.g.,a compound of formula (I)) is least 97% enantiomeric excess of the Rstereoisomer. In some embodiments, the compound described herein (e.g.,a compound of formula (I)) is at least 99% enantiomeric excess of the Rstereoisomer.

In certain embodiments, the compound described herein (e.g., a compoundof formula (I)) is at least 10% enantiomeric excess of the Sstereoisomer. In certain embodiments, the compound described herein(e.g., a compound of formula (I)) is at least 50% enantiomeric excess ofthe S stereoisomer. In some embodiments, the compound described herein(e.g., a compound of formula (I)) is at least 75% enantiomeric excess ofthe S stereoisomer. In some embodiments, the compound described herein(e.g., a compound of formula (I)) is at least 85% enantiomeric excess ofthe S stereoisomer. In some embodiments, the compound described herein(e.g., a compound of formula (I)) is at least 90% enantiomeric excess ofthe S stereoisomer. In some embodiments, the compound described herein(e.g., a compound of formula (I)) is at least 95% enantiomeric excess ofthe S stereoisomer. In some embodiments, the compound described herein(e.g., a compound of formula (I)) is at least 97% enantiomeric excess ofthe S stereoisomer. In some embodiments, the compound described herein(e.g., a compound of formula (I)) is at least 99% enantiomeric excess ofthe S stereoisomer.

In certain embodiments, the compound of formula (I) is represented bythe following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9. Insome embodiments, n is 10. In some embodiments, n is 11. In someembodiments, n is 12.

In some embodiments, the compound of formula (I) is represented by thefollowing formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some aspects of thisembodiment, n is an integer from 4 to 10. In some embodiments, n is 6.In some embodiments, n is 7. In some embodiments, n is 8. In someembodiments, n is 9. In some embodiments, n is 10. In some embodiments,n is 11. In some embodiments, n is 12.

In some embodiments, the compound of formula (I) is represented by thefollowing formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9. Insome embodiments, n is 10. In some embodiments, n is 11. In someembodiments, n is 12.

In certain embodiments, the compound of formula (I) may have an averagemolecular weight ranging from about 300 daltons to about 2000 daltons(e.g., from about 300 daltons to about 1500 daltons, from about 400daltons to about 1200 daltons, from about 500 daltons to about 1000daltons, from about 600 daltons to about 850 daltons).

The polymeric portion of a compound of formula (I) described herein mayhave a polymer polydispersity index (PDI) of less than or equal to about2.5 (e.g., less than or equal to about 2.2, less than or equal to about2.0, or less than or equal to about 1.5). In some embodiments, ahydrophobic polymer described herein may have a polymer PDI of about 1.0to about 2.5, about 1.0 to about 2.0, about 1.0 to about 1.7, or fromabout 1.0 to about 1.6.

In another aspect, the invention is directed to a composition (e.g., apharmaceutical composition) comprising a compound of formula (I).

In certain embodiments, the composition is substantially free of fattyalcohols (e.g., polidocanol). In some embodiments, the composition issubstantially free of lactic acid or esters thereof (e.g., lactic acidmethyl ester or lactic acid ethyl ester). In some embodiments, thecomposition is substantially free of a second sclerosant (e.g., a secondcompound for the treatment of varicose veins).

In some embodiments, the composition comprises an additional therapeuticagent. In certain embodiments, an additional therapeutic agent comprisesan analgesic (e.g., fentanyl, morphine or codeine). In some embodiments,an additional therapeutic agent comprises an anti-inflammatory (e.g.,ibuprofen or naproxen). In some embodiments, an additional therapeuticagent comprises an anesthetic (e.g., benzocaine or lidocaine). In someembodiments, an additional therapeutic agent comprises an opiod.

In certain embodiments, at least 50% by weight of the composition is acompound of formula (I). In some embodiments, at least 75% by weight ofthe composition is a compound of formula (I). In some embodiments, atleast 85% by weight of the composition is a compound of formula (I). Insome embodiments, at least 90% by weight of the composition is acompound of formula (I). In some embodiments, at least 95% by weight ofthe composition is a compound of formula (I). In some embodiments, atleast 97% by weight of the composition is a compound of formula (I). Insome embodiments, the composition consists essentially of a compound offormula (I).

In certain embodiments, the composition comprises a racemic mixture ofthe compound of formula (I) (e.g., less than 10% enantiomeric excess ofeither the R or S stereoisomer). In certain embodiments, the compositioncomprises at least 10% enantiomeric excess of an R stereoisomer of acompound of formula (I). In certain embodiments, the compositioncomprises at least 50% enantiomeric excess of an R stereoisomer of acompound of formula (I). In some embodiments, the composition comprisesat least 75% enantiomeric excess of an R stereoisomer of a compound offormula (I). In some embodiments, the composition comprises at least 85%enantiomeric excess of an R stereoisomer of a compound of formula (I).In some embodiments, the composition comprises at least 90% enantiomericexcess of an R stereoisomer of a compound of formula (I). In someembodiments, the composition comprises at least 95% enantiomeric excessof an R stereoisomer of a compound of formula (I). In some embodiments,the composition comprises at least 97% enantiomeric excess of an Rstereoisomer of a compound of formula (I). In some embodiments, thecomposition comprises at least 99% enantiomeric excess of an Rstereoisomer of a compound of formula (I).

In certain embodiments, the composition comprises at least 10%enantiomeric excess of an S stereoisomer of a compound of formula (I).In certain embodiments, the composition comprises at least 50%enantiomeric excess of an S stereoisomer of a compound of formula (I).In some embodiments, the composition comprises at least 75% enantiomericexcess of an S stereoisomer of a compound of formula (I). In someembodiments, the composition comprises at least 85% enantiomeric excessof an S stereoisomer of a compound of formula (I). In some embodiments,the composition comprises at least 90% enantiomeric excess of an Sstereoisomer of a compound of formula (I). In some embodiments, thecomposition comprises at least 95% enantiomeric excess of an Sstereoisomer of a compound of formula (I). In some embodiments, thecomposition comprises at least 97% enantiomeric excess of an Sstereoisomer of a compound of formula (I). In some embodiments, thecomposition comprises at least 99% enantiomeric excess of an Sstereoisomer of a compound of formula (I).

In certain embodiments, the compound of formula (I) is represented bythe following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In some embodiments, the compound of formula (I) is represented by thefollowing formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In some embodiments, the compound of formula (I) is represented by thefollowing formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In certain embodiments, the composition is in the form of anoil-in-water emulsion. In some embodiments, the composition is in theform of a water-in-oil emulsion. In some embodiments, the composition isin the form of a thickened aqueous gel. In some embodiments, thecomposition is in the form of a hydrophilic gel. In some embodiments,the composition is in the form of a capsule. In some embodiments, thecomposition is in the form of a tablet. In some embodiments, thecomposition is in the form of a hydrophobic ointment. In someembodiments, the composition is in the form of a hydrophilic ointment.In some embodiment, the composition is in the form of an anhydrous gel.In some embodiments, the composition is in the form of a solution. Insome embodiments, the composition is in the form of an injectable foam.

In certain embodiments, the composition is configured for topicaladministration. In some embodiments, the composition is configured fororal administration. In some embodiments, the composition is configuredfor administration in the form of a gel, ointment, cream or patch (e.g.,the composition is applied to a mounting that can be adhered to the skinof a subject). In some embodiments, the composition is configured forparenteral administration (e.g., the composition is prepared as asterile solution using isotonic saline, Ringer's solution, water forinjection (WFI) and sterile water for injection (SWFI)).

In another aspect, the present invention is directed to a method oftreating varicose veins, the method comprising administering a compoundof formula (I) or composition described herein.

In certain embodiments, the compound is administered topically. In someembodiments, the compound is administered via a gel, ointment, cream orpatch. In certain embodiments, the composition is administeredtopically. In some embodiments, the composition is administered via agel, ointment, cream or patch.

In certain embodiments, the method comprises administering a compound offormula (I) or composition as described herein once daily. In someembodiments, the method comprises administering a compound of formula(I) or composition as described herein twice daily. In some embodiments,the method comprises administering a compound of formula (I) orcomposition as described herein three times daily. In some embodiments,the method comprises administering a compound of formula (I) orcomposition as described herein four times daily. In some embodiments,the method comprises administering a compound of formula (I) orcomposition as described herein five times daily. In certainembodiments, the method comprises administering a compound of formula(I) or composition as described herein once weekly. In some embodiments,the method comprises administering a compound of formula (I) orcomposition as described herein once monthly.

In certain embodiments, the method includes a compound of formula (I)represented by the following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In some embodiments, the method includes a compound of formula (I)represented by the following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In some embodiments, the method includes a compound of formula (I)represented by the following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In certain embodiments, the method includes a composition including acompound of formula (I) represented by the following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In certain embodiments, the method includes a composition including acompound of formula (I) represented by the following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In certain embodiments, the method includes a composition including acompound of formula (I) represented by the following formula:

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In certain embodiments, the composition is administered topically. Insome embodiments, the composition is administered via a patch. In someembodiments, the composition is administered orally. In someembodiments, the composition is administered parenterally (e.g.,subcutaneous, intramuscular or intravenous injection).

In another aspect, the present invention is directed to a method ofmaking a compound of formula (I), the method comprising reacting a fattyalcohol of formula (II):

wherein

n is an integer from 2 to 35; and

R¹ is a C₈₋₃₅ alkyl;

with an α-hydroxy ester in the presence of enzymatic conditions ingreater than 60% purity.

In certain embodiments, n is an integer from 2 to 25. In some aspects ofthis embodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10.

In certain embodiments, R¹ is a C₈₋₂₅ alkyl group. In some embodiments,R¹ is a C₁₀₋₂₀ alkyl group. In some embodiments, R¹ is a C₁₀₋₁₅ alkylgroup. In some embodiments, R¹ is a C₁₂ alkyl group.

In certain embodiments, the method of making a compound of formula (I)is carried out in an open reaction vessel.

In certain embodiments, the method includes removing one of the productsof the method. In some embodiments, the product is an alcohol. Incertain embodiments, the product is an alcohol by-product. In someembodiments, the product is removed by using at least one of thefollowing: evaporation under ambient conditions, evaporation facilitatedby heat, rotary evaporation, convection, inert gas flow, application ofvacuum, vacuum filtration, distillation, azeotropic distillation, vacuumdistillation, chemical modification, enzymatic modification andadsorption.

In certain embodiments, the reaction is carried out on at least 50 g ofthe saturated alcohol starting material. In some embodiments, thereaction is carried out on at least 100 g of the saturated alcoholstarting material. In some embodiments, the reaction is carried out onat least 200 g of the saturated alcohol starting material. In someembodiments, the reaction is carried out on at least 250 g of thesaturated alcohol starting material. In some embodiments, the reactionis carried out on at least 400 g of the saturated alcohol startingmaterial. In some embodiments, the reaction is carried out on at least500 g of the saturated alcohol starting material.

In certain embodiments, the method comprises a batch process ofproducing a compound of formula (I).

In certain embodiments, the desired compound is produced in greater than60% purity in the absence of a purification step. In some embodiments,the desired compound is produced in greater than 70% purity. In someembodiments, the desired compound is produced in greater than 70% purityin the absence of a purification step. In some embodiments, the desiredcompound is produced in greater than 80% purity. In some embodiments,the desired compound is produced in greater than 80% purity in theabsence of a purification step. In some embodiments, the desiredcompound is produced in greater than 90% purity. In some embodiments,the desired compound is produced in greater than 90% purity in theabsence of a purification step. In some embodiments, the desiredcompound is produced in greater than 95% purity. In some embodiments,the desired compound is produced in greater than 95% purity in theabsence of a purification step. In some embodiments, the desiredcompound is produced in the absence of a purification step.

In certain embodiments, the saturated alcohol is polidocanol (also knownas polydocanol). In some embodiments, the α-hydroxy ester is ethyllactate. In some embodiments, the ethyl lactate is substantially the Rstereoisomer. In some embodiments, the ethyl lactate is substantiallythe S stereoisomer. In some embodiments, the enzyme is a lipase enzyme.In some embodiments, the lipase enzyme is Novozym 435®.

In another aspect, the present invention is directed to a method ofmaking a compound of formula (I), the method comprising reacting a fattyalcohol of formula (II):

wherein

n is an integer from 2 to 35; and

R¹ is a C₈₋₃₅ alkyl;

with an α-hydroxy ester in the presence of enzymatic conditions ingreater than 60% yield.

In certain embodiments, the desired compound is produced in greater than70% yield. In some embodiments, the desired compound is produced ingreater than 80% yield. In some embodiments, the desired compound isproduced in greater than 90% yield. In some embodiments, the desiredcompound is produced in greater than 95% yield.

wherein n is an integer from 2 to 35. In some aspects of thisembodiment, n is an integer from 2 to 25. In some aspects of thisembodiment, n is an integer from 2 to 15. In some aspects of thisembodiment, n is an integer from 2 to 10. In some embodiments, n is aninteger from 4 to 10. In some embodiments, n is 6. In some embodiments,n is 7. In some embodiments, n is 8. In some embodiments, n is 9.

In certain embodiments, R¹ is a C₈₋₂₅ alkyl group. In some embodiments,R¹ is a C₁₀₋₂₀ alkyl group. In some embodiments, R¹ is a C₁₀₋₁₅ alkylgroup. In some embodiments, R¹ is a C₁₂ alkyl group.

In some embodiments, the a-hydroxy ester is ethyl lactate. In someembodiments, the ethyl lactate is substantially the R stereoisomer. Insome embodiments, the ethyl lactate is substantially the S stereoisomer.

Definitions

Definitions of specific functional groups and chemical terms aredescribed in more detail below. For purposes of this invention, thechemical elements are identified in accordance with the Periodic Tableof the Elements, CAS version, Handbook of Chemistry and Physics, 75^(th)Ed., inside cover, and specific functional groups are generally definedas described therein. Additionally, general principles of organicchemistry, as well as specific functional moieties and reactivity, aredescribed in Organic Chemistry, Thomas Sorrell, University ScienceBooks, Sausalito, 1999; Smith and March March's Advanced OrganicChemistry, 5^(th) Edition, John Wiley & Sons, Inc., New York, 2001;Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., NewYork, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3^(rd)Edition, Cambridge University Press, Cambridge, 1987; the entirecontents of each of which are incorporated herein by reference.

The term “halo” or “halogen” refers to any radical of fluorine,chlorine, bromine or iodine.

The term “alkyl” refers to a hydrocarbon chain that may be a straightchain or branched chain, containing the indicated number of carbonatoms. For example, C₁-C₁₂ alkyl indicates that the group may have from1 to 12 carbon atoms in it. The term “haloalkyl” refers to an alkyl inwhich one or more hydrogen atoms are replaced by halo, and includesalkyl moieties in which all hydrogens have been replaced by halo, e.g.,perfluoroalkyl. The terms “arylalkyl” or “aralkyl” refer to an alkylmoiety in which an alkyl hydrogen atom is replaced by an aryl group.Aralkyl includes groups in which more than one hydrogen atom has beenreplaced by an aryl group. Examples of “arylalkyl” or “aralkyl” includebenzyl, 2-phenylethyl, 3-phenylpropyl, 9-fluorenyl, benzhydryl, andtrityl groups.

The term “alkylene” refers to a divalent alkyl, e.g., —CH₂—, —CH₂CH₂—,and —CH₂CH₂CH₂—.

The term “alkenyl” refers to a straight or branched hydrocarbon chaincontaining 2-12 carbon atoms and having one or more double bonds.Examples of alkenyl groups include, but are not limited to, allyl,propenyl, 2-butenyl, 3-hexenyl and 3-octenyl groups. One of the doublebond carbons may optionally be the point of attachment of the alkenylsubstituent. The term “alkynyl” refers to a straight or branchedhydrocarbon chain containing 2-12 carbon atoms and characterized inhaving one or more triple bonds. Examples of alkynyl groups include, butare not limited to, ethynyl, propargyl, and 3-hexynyl. One of the triplebond carbons may optionally be the point of attachment of the alkynylsubstituent.

The term “aryl” refers to an aromatic monocyclic, bicyclic, or tricyclichydrocarbon ring system, wherein any ring atom capable of substitutioncan be substituted, e.g., by one or more substituents. Examples of arylmoieties include, but are not limited to, phenyl, naphthyl, andanthracenyl.

The term “arylalkyl” or the term “aralkyl” refers to alkyl substitutedwith an aryl. Exemplary aralkyls include but are not limited to benzyland phenethyl.

The term “cycloalkyl” as employed herein includes saturated cyclic,bicyclic, tricyclic or polycyclic hydrocarbon groups having 3 to 12carbons. Any ring atom can be substituted, e.g., by one or moresubstituents. The cycloalkyl groups can contain fused rings. Fused ringsare rings that share a common carbon atom. Examples of cycloalkylmoieties include, but are not limited to, cyclopropyl, cyclohexyl,methylcyclohexyl, adamantyl, and norbornyl.

The term “emollient” is a hydrophobic material that provides softness,lubricity and smoothness to the skin and often forms a thin occlusivefilm which increases hydration by reducing transepidermal water loss(TEWL).

The “enantiomeric excess” or “% enantiomeric excess” of a compositioncan be calculated using the equation shown below. In the example shownbelow a composition contains 90% of one enantiomer, e.g., the Senantiomer, and 10% of the other enantiomer, i.e., the R enantiomer.

cc=(90−10)/100=80%.

Thus, a composition containing 90% of one enantiomer and 10% of theother enantiomer is said to have an enantiomeric excess of 80%. Some ofthe compositions described herein contain an enantiomeric excess of atleast 50%, 75%, 90%, 95%, or 99% (the S-enantiomer). In other words thecompositions contain an enantiomeric excess of the S enantiomer over theR enantiomer.

The term “heterocyclyl” refers to a nonaromatic 3-10 memberedmonocyclic, 8-12 membered bicyclic, or 11-14 membered tricyclic ringsystem having 1-3 heteroatoms if monocyclic, 1-6 heteroatoms ifbicyclic, or 1-9 heteroatoms if tricyclic, said heteroatoms selectedfrom O, N, Si, P or S, e.g., carbon atoms and 1-3, 1-6, or 1-9heteroatoms of N, O, Si, P or S if monocyclic, bicyclic, or tricyclic,respectively. The heteroatom may optionally be the point of attachmentof the heterocyclyl substituent. Any ring atom can be substituted, e.g.,by one or more substituents. The heterocyclyl groups can contain fusedrings. Fused rings are rings that share a common carbon atom. Examplesof heterocyclyl include, but are not limited to, tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholino, pyrrolinyl, pyrimidinyl,quinolinyl, and pyrrolidinyl.

The term “heteroaryl” refers to an aromatic 5-8 membered monocyclic,8-12 membered bicyclic, or 11-14 membered tricyclic ring system having1-3 heteroatoms if monocyclic, 1-6 heteroatoms if bicyclic, or 1-9heteroatoms if tricyclic, said heteroatoms selected from O, N, Si, P orS, e.g., carbon atoms and 1-3, 1-6, or 1-9 heteroatoms of N, O, Si, P orS if monocyclic, bicyclic, or tricyclic, respectively. Any ring atom canbe substituted, e.g., by one or more substituents.

The term “humectant” is a polar hygroscopic material that increaseshydration by drawing water from the environment to help retain water inthe skin's upper layers.

The term “moisturizer” refers to a material that will increase the levelof hydration of skin, mucous membrane, wound, lesion or scab.

As used herein, “polymer polydispersity index (PDI)” or “polymerpolydispersity” refers to the distribution of molecular mass in a givenpolymer sample. The polymer PDI calculated is the weight averagemolecular weight divided by the number average molecular weight. Itindicates the distribution of individual molecular masses in a batch ofpolymers. The polymer PDI has a value typically greater than 1, but asthe polymer chains approach uniform chain length, the PDI approachesunity (1).

The term “sclerosant” refers to an injectable irritant that is used inthe treatment of varicose veins and that causes inflammation andsubsequent fibrosis.

The term “substantially free” when referring to a compound orcomposition described herein means that there is less than 20% (byweight) of the designated compound or by-product (e.g., a saturatedalcohol starting material) present, more preferably, there is less than10% (by weight) of the designated compound or by-product, morepreferably, there is less than 9% (by weight) of the designated compoundor by-product, more preferably, there is less than 8% (by weight) of thedesignated compound or by-product, more preferably, there is less than7% (by weight) of the designated compound or by-product, morepreferably, there is less than 6% (by weight) of the designated compoundor by-product, more preferably, there is less than 5% (by weight) of thedesignated compound or by-product, more preferably, there is less than4% (by weight) of the designated compound or by-product, morepreferably, there is less than 3% (by weight) of the designated compoundor by-product, more preferably, there is less than 2% (by weight) of thedesignated compound or by-product, and most preferably, there is lessthan 1% (by weight) of the designated compound or by-product.

The term “substituents” refers to a group “attached” to a alkyl,cycloalkyl, alkenyl, alkynyl, heterocyclyl, heterocycloalkenyl,cycloalkenyl, aryl, or heteroaryl group at any atom of that group.Suitable substituents include, without limitation, alkyl, e.g., C1, C2,C3, C4, C5, C6, C7, C8, C9, C10, C11, C12 straight or branched chainalkyl, cycloalkyl, haloalkyl, e.g., perfluoroalkyl such as CF₃, aryl,heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, alkenyl, alkynyl,cycloalkenyl, heterocycloalkenyl, alkoxy, haloalkoxy, e.g.,perfluoroalkoxy such as OCF₃, halo, hydroxy, carboxy, carboxylate,cyano, nitro, amino, alkyl amino, SO₃H, sulfate, phosphate,methylenedioxy e.g., —O—CH₂—O—, ethylenedioxy, oxo, thioxo, e.g., C═S,imino, e.g., alkyl, aryl, aralkyl, S(O)_(n)alkyl, S(O)_(n) aryl,S(O)_(n) heteroaryl, S(O)_(n) heterocyclyl, i.e., wherein n is aninteger between 0 and 2, amine, e.g., mono-, di-, alkyl, cycloalkyl,aralkyl, heteroaralkyl, aryl, heteroaryl, and combinations thereof,ester, e.g., alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, amide,e.g., mono-, di-, alkyl, aralkyl, heteroaralkyl, aryl, heteroaryl, andcombinations thereof, sulfonamide, e.g., mono-, di-, alkyl, aralkyl,heteroaralkyl, and combinations thereof. In one aspect, the substituentson a group are independently any one single, or any subset of theaforementioned substituents. In another aspect, a substituent may itselfbe substituted with any one of the above substituents.

DETAILED DESCRIPTION Compounds

In general, the compounds utilized in the composition of the presentapplication are represented by formula (I):

wherein n, R¹ and R² are as represented herein.

In one aspect, the invention features a composition containing anenantiomeric excess (ee) of the compound of Formula (I). For example,the composition can contain an ee of at least 50%, 75%, 90%, 95%, or99%.

A compound described herein can also be in the form of a prodrug.Prodrugs of the compounds described herein are those compounds thatreadily undergo chemical changes under physiological conditions toprovide the compounds of the present invention. In another exemplaryembodiment, the prodrug is suitable for treatment/prevention of thosediseases and conditions that require the drug molecule to cross theblood brain bather. In a preferred embodiment, the prodrug enters thebrain, where it is converted into the active form of the drug molecule.Additionally, prodrugs can be converted to the compounds of the presentinvention by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to the compounds of thepresent invention when placed in a transdermal patch reservoir with asuitable enzyme or chemical reagent.

A compound of the present invention can exist in an unsolvated form aswell as a solvated form, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are encompassedwithin the scope of the present invention. Certain compounds of thepresent invention may exist in multiple crystalline or amorphous formstermed polymorphic forms. In general, all physical forms are of use inthe methods contemplated by the present invention and are intended to bewithin the scope of the present invention. “Compound or apharmaceutically acceptable salt, hydrate, polymorph or solvate of acompound” intends the inclusive meaning of “or”, in that materialsmeeting more than one of the stated criteria included, for example, amaterial that is both a salt and a solvate is encompassed.

A compound described herein can be in the form of a metabolite. Ametabolite may be a compound that is related to a compound describedherein, as a form of such compound obtained in a human or animal body byaction of the body on the administered form of the compound. Forexample, a metabolite may be a de-methylated analogue of a compoundbearing a methyl group, which is obtained in the body afteradministration of the methylated compound as a result of action by thebody on the methylated compound. A metabolite may also be acarboxylic-acid containing compound, which is obtained in the body afteradministration of the corresponding ester as a result of action by thebody on the ester-containing compound.

Compositions of the Invention

The present invention features pharmaceutical compositions including anyof the compounds described herein, either alone or in combination withone or more excipients. In some embodiments, the pharmaceuticalcomposition is a composition that can be administered topically. In someembodiments, the pharmaceutical composition is a composition that can beadministered to a subject orally. In some embodiments, the compositionis a composition that can be administered bucally, vaginally, mucosally,nasally (e.g., intranasally) or parenterally (such as subcutaneous,intramuscular or intravenous injection), e.g., a liquid composition suchas a solution, intranasally or via patch. In some embodiments, thecomposition is a solid composition, for example, a lyophilisate, whichcan be further processed prior to administering the composition to asubject, for example, the solid composition can be further processed toform a liquid composition such as a solution.

The compositions described herein, e.g., a composition including acompound of formula (I), can be used as sclerosant composition. Thesecompositions may also include one or more analgesics, anesthetics and/oranti-inflammatory compounds.

Exemplary analgesic compounds include, but are not limited to, codeine,hydrocodone, hydromorphone, levorpharnol, morphine, oxycodone,oxymorphone, butorphanol, dezocine, nalbuphine, pentazocine, etodolac,indomethacin, sulindac, tolmetin, nabumetone, piroxicam, acetaminophen,fenoprofen, flurbiprofen, ibuprofen, ketoprofen, naproxen, diclofenac,oxaprozin, aspirin, diflunisal, meclofenamic acid, mefanamic acid,prednisolone, and dexamethasone.

Exemplary anesthetic compounds include, but are not limited to,benzocaine, butamben, dibucaine, lidocaine, oxybuprocaine, pramoxine,proparacaine, proxymetacaine, and tetracaine.

Exemplary anti-inflammatory compounds include, but are not limited to,aspirin, naproxen, ibuprofen, etodolac, cortisone (corticosteroids),antacids, sucralfate, proton-pump inhibitors, misoprostol, methotrexate,sulfasalazine, D-penicillamine, azathioprine, cyclophosphamide,chlorambucil, cyclosporine, leflunomide, etanercept, infliximab,anakinra, adalimumab, an NSAID and/or hydroxychloroquine.

In some embodiments, the compositions described herein consistessentially of a compound of formula (I). Certain compositions may alsoinclude one or more external analgesics and/or one or more moisturizers.

The compositions described herein, e.g., a composition including acompound of formula (I), may be used for treating or preventing varicoseveins. The compositions are useful for topically treating topicalvaricose veins (e.g., in the form of a topical cream or ointment).Certain compositions described herein adhere well to the skin and thusare very effective topically. Certain methods involve topicalapplication, particularly to skin.

Exemplary compositions may include one or more additional excipients.Said excipients may be selected from, but not limited to moisturizers,skin protectants, enhancer components, surfactants, and thickeners.

Moisturizers

Compositions of the present invention may include a moisturizer toincrease the level of hydration of the skin. The moisturizer can be ahydrophilic material including humectants or it can be a hydrophobicmaterial including emollients. A humectant is a polar hygroscopicmaterial that increases hydration by drawing water from the environmentto help retain water in the skin's upper layers. An emollient is ahydrophobic material that provides softness, lubricity and smoothness tothe skin and often forms a thin occlusive film that increases hydrationby reducing transepidermal water loss (TEWL). Exemplary hydrophilicmoisturizers include, but are not limited to, water, polyhydricalcohols, lower alkyl ethers, N-methylpyrrolidone, lower alkyl esters,urea, amino acids, ethoxylated amides, sodium pyrrolidone carboxylicacid, and the lower monohydroxy alcohols and hydroxy acids discussedbelow as enhancers, as well as combinations thereof. Thus, a lowermonohydroxy alcohol can function as both a hydrophilic compound and anenhancer. Preferably, the hydrophilic components include polyhydricalcohols, lower alkyl ethers, and short chain esters. More preferably,the hydrophilic components include polyhydric alcohols.

Exemplary hydrophobic moisturizers include, but are not limited to,short chain (i.e., C1-C6) alkyl or (C6-C12) aryl esters of long (i.e.,C8-C36) straight or branched chain alkyl or alkenyl alcohols or acidsand polyethoxylated derivatives of the alcohols; short chain (i.e.,C1-C6) alkyl or (C6-C12) aryl esters of (C4-C12) diacids or (C4-C12)diols optionally substituted in available positions by —OH; (C2-C18)alkyl or (C6-C12) aryl esters of glycerol, pentaerythritol, ethyleneglycol, propylene glycol, as well as polyethoxylated derivatives ofthese; (C12-C22) alkyl esters or (C12-C22) ethers of polypropyleneglycol; (C12-C22) alkyl esters or (C12-C22) ethers of polypropyleneglycol/polyethylene glycol copolymer; and polyether polysiloxanecopolymers. Additional examples of hydrophobic components include cyclicdimethicones, including volatile cyclic silicones such as D4 and D5,polydialkylsiloxanes, polyaryl/alkylsiloxanes, silicone copolyols, cocoabutter, beeswax, jojoba oil, lanolin and derivatives, long chain (i.e.,C8-C36) alkyl and alkenyl esters of long (i.e., C8-C18) straight orbranched chain alkyl or alkenyl alcohols or acids, long chain (i.e.,C8-C36) alkyl and alkenyl amides of long straight or branched chain(i.e., C8-C36) alkyl or alkenyl amines or acids; hydrocarbons includingstraight and branched chain alkanes and alkenes such as isoparafins(e.g., isooctane, isododecane, isooctadecane, etc.), squalene, andmineral oil, polysiloxane polyalkylene copolymers, dialkoxy dimethylpolysiloxanes; (C12-C22) alkyl and (C12-C22) alkenyl alcohols, andpetroleum derived alkanes such as isoparafins, petrolatum, petrolatumUSP, as well as refined natural oils (especially NF or USP grades) suchas olive oil NF, cotton seed oil, castor oil, peanut oil, corn oil,seasame oil, safflower oil, soybean oil, sunflower oil and the like, andblends thereof. In certain preferred embodiments, the hydrophobiccomponents useful in the compositions of the present invention includethose selected from the group consisting of petrolatum USP and shortchain (i.e., C1-C6) alkyl or (C6-C12) aryl esters of long (i.e., C8-C36)straight or branched chain alkyl or alkenyl alcohols or acids andpolyethoxylated derivatives of the alcohols; short chain (i.e., C1-C6)alkyl or (C6-C12) aryl esters of (C4-C12) diacids or (C4-C12) diolsoptionally substituted in available positions by —OH (such asdiisopropyladipate, diisopropylsebacate); (C1-C9) alkyl or (C6-C12) arylesters of glycerol, pentaerythritol, ethylene glycol, propylene glycol(such as glyceryl tricaprylate/caprate); and mixtures thereof.

Skin Protectants

Compositions of the present invention may also include a skinprotectant. Certain materials including some humectants or emollientsare also useful at providing safe and effective skin protection. Whenused in the appropriate amount they temporarily protect injured orexposed skin from harmful stimuli and may help provide relief to suchsurfaces. Similarly, sunscreens may be included, which protect the skinfrom harmful ultraviolet radiation. Information concerning safe andeffective skin protectants is provided in the Proposed Final Rulemakingfor Fever Blister and Cold Sore Treatment Drug Products in the SkinProtectant Drug Products for Over-the-counter Human Use Monograph,published by the United States Food and Drug Administration in theFederal Register, Volume 51, Number 21, Jan. 31, 1990, pages 3362 to3370.

Enhancer Component

Compositions of the present invention may optionally include an enhancerto protect against microbial activity (e.g., against gram negativebacteria). The enhancer component may include but is not limited to analpha-hydroxy acid, a beta-hydroxy acid, other carboxylic acids, a(C1-C4) alkyl carboxylic acid, a (C6-C12) aryl carboxylic acid, a(C6-C12) aralkyl carboxylic acid, a (C6-C12) alkaryl carboxylic acid, aphenolic compound (such as certain antioxidants and parabens), a(C1-C10) monohydroxy alcohol, a chelating agent, or a glycol ether(i.e., ether glycol) and/or mixtures thereof.

Surfactants

Compositions of the present invention optionally may include one or moresurfactants to emulsify the composition and to help wet the surfaceand/or to aid in contacting the microorganisms. In general, a“surfactant” refers to an amphiphile (i.e., a molecule possessing bothpolar and nonpolar regions which are covalently bound) capable ofreducing the surface tension of water and/or interfacial tension betweenwater and an immiscible liquid. Surfactants that may be employed in thepresent compositions include, but are not limited to include soaps,detergents, emulsifiers, surface active agents, and the like. Thesurfactant can be cationic, anionic, nonionic, or amphoteric. Inpreferred embodiments, the surfactant includes poloxamer, ethoxylatedstearates, sorbitan oleates, high molecular weight crosslinkedcopolymers of acrylic acid and a hydrophobic comonomer, and cetyl andstearyl alcohols as cosurfactants.

Thickeners

Compositions of the present invention may also include thickeners thatare soluble, swellable, or insoluble organic polymeric thickeners suchas natural and synthetic polymers including polyacrylic acids,poly(N-vinyl pyrrolidones), cellulosic derivatives, silicone elastomersand xanthan or guar gums or inorganic thickeners such as silica, fumedsilica, precipitated silica, silica aerogel and carbon black, and thelike; other particle fillers such as calcium carbonate, magnesiumcarbonate, kaolin, talc, titanium dioxide, aluminum silicate,diatomaceous earth, ferric oxide and zinc oxide, clays, and the like;ceramic microspheres or glass microbubbles; ceramic microspheres such asthose available under the tradenames “ZEOSPHERES” or “Z-LIGHT” from 3MCompany, St. Paul, Minn. and/or combinations thereof.

Forms

The pharmaceutical compositions of this invention may be administeredorally. Compositions suitable for oral administration may be in the formof capsules, cachets, pills, tablets, lozenges (using a flavored base,usually sucrose and acacia or tragacanth), powders, granules, or as asolution or a suspension in an aqueous or non-aqueous liquid, or as anoil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup,or as pastilles (using an inert base, such as gelatin and glycerin, orsucrose and acacia) and/or as mouth washes and the like, each containinga predetermined amount of a compound of the invention(s) as an activeingredient.

The tablets, and other solid dosage forms of the pharmaceuticalcompositions of the present invention, such as dragees, capsules, pillsand granules, may optionally be scored or prepared with coatings andshells, such as enteric coatings and other coatings well known in thepharmaceutical-formulating art. They may also be formulated so as toprovide slow or controlled release of the active ingredient thereinusing, for example, hydroxypropylmethyl cellulose in varying proportionsto provide the desired release profile, other polymer matrices,liposomes and/or microspheres. They may be sterilized by, for example,filtration through a bacteria-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved in sterile water, or some other sterile injectable mediumimmediately before use. These compositions may also optionally containpacifying agents and may be of a composition that they release theactive ingredient(s) only, or preferentially, in a certain portion ofthe gastrointestinal tract, optionally, in a delayed manner Examples ofembedding compositions which can be used include polymeric substancesand waxes. The active ingredient can also be in micro-encapsulated form,if appropriate, with one or more of the above-described excipients.

In addition, the compositions described herein may be administeredtopically, transdermally, rectally, vaginally, parentally, intranasally,intrapulmonary, intraocularly, intravenously, intramuscularly,intraarterially, intrathecally, intracapsularly, intraorbitally,intracardiacly, intradermally, intraperitoneally, transtracheally,subcutaneously, subcuticularly, intraarticularly, subcapsularly,subarachnoidly, intraspinally, intrasternally or by inhalation.

Generally, the compositions of this invention may also be in one of thefollowing forms:

A hydrophobic or hydrophilic ointment wherein the composition isformulated with a hydrophobic base (e.g., petroleum, thickened or gelledwater-insoluble oils, etc.) and optionally having a minor amount of awater soluble phase. Hydrophilic ointments generally contain one or moresurfactants or wetting agents.

An oil-in-water emulsion wherein the compositions described may beformulated in which the antiviral component is emulsified into anemulsion comprising a discrete phase of a hydrophobic component and acontinuous aqueous phase that includes water and optionally one or morepolar hydrophilic material(s) as well as salts, surfactants, emulsifiersand other components. These emulsions may include water soluble orwater-swellable polymers as well as one or more emulsifiers that help tostabilize the emulsion. These emulsions generally have higherconductivity values, as disclosed in U.S. Pat. No. 7,030,203.

A water-in-oil emulsion wherein the compositions described herein may beformulated so that the antiviral components are incorporated into anemulsion that includes a continuous phase of a hydrophobic component andan aqueous phase that includes water and optionally one or more polarhydrophilic material(s) as well as salts or other components. Theseemulsions may include oil-soluble or oil-swellable polymers as well asone or more emulsifier(s) that help to stabilize the emulsion.

Thickened aqueous gels refer to systems including an aqueous phase whichhas been thickened by suitable natural, modified natural or syntheticpolymers as described herein. Alternatively, the thickened aqueous gelscan be thickened using suitable polyethoxylated alkyl chain surfactantsthat effectively thicken the composition as well as other non-ionic,cationic or anionic emulsifier systems.

Hydrophilic gels refer to systems in which the continuous phase includesat least one water soluble or water dispersible hydrophilic componentother than water. The formulations may optionally also contain water upto 20% by weight. Higher levels may be suitable in some compositions.Suitable hydrophilic components include one or more glycols such aspolyols such as glycerin, propylene glycol, butylene glycols,polyethylene glycols (PEGS), random or block copolymers of ethyleneoxide, propylene oxide, and/or butylene oxide, polyalkoxylatedsurfactants having one or more hydrophobic moieties per molecule,silicone copolyols, as well as combinations thereof. One of ordinaryskill in the art will recognize and understand that the level ofethoxylation should be sufficient to render the hydrophilic componentwater soluble or water dispersible at 23° C. In most embodiments, thewater content is less than 20%, preferably less than 10% and preferablyless than 5% by weight of the composition.

Methods of Making Compounds as Described Herein

The compounds described herein and employed in the compositionsdescribed herein (e.g., a compound of formula I) can be made using avariety of synthetic techniques. One example of a preparation of thecompounds described herein is illustrated below in Scheme 1.

As can be appreciated by the skilled artisan, methods of synthesizingthe compounds of the formulae herein will be evident to those ofordinary skill in the art. Additionally, any synthetic steps describedherein may be performed in an alternate sequence or order to give thedesired compounds. Synthetic chemistry transformations and protectinggroup methodologies, i.e., protection and deprotection, useful insynthesizing the compounds described herein are known in the art andinclude, for example, those such as described in R. Larock,Comprehensive Organic Transformations, VCH Publishers (1989); T. W.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2d.Ed., John Wiley and Sons (1991); L. Fieser and M. Fieser, Fieser andFieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); andL. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, JohnWiley and Sons (1995), and subsequent editions thereof.

Reaction Mixtures

The present invention refers to compositions comprising a compound asdescribed herein, including a reaction mixture, e.g., a reaction mixturethat is present during a method or process described herein.

In certain embodiments, the methods described herein further comprise asolvent. In certain embodiments, the solvent is an organic solvent. Incertain embodiments, the solvent is an aprotic solvent. Exemplaryorganic solvents include, but are not limited to, benzene, toluene,xylenes, acetonitrile, acetone, ethyl ether, tetrahydrofuran, methylenechloride, dichloroethane and chloroform, or a mixture thereof. Incertain embodiments, the solvent is acetonitrile. In certainembodiments, the solvent is methylene chloride. In certain embodiments,the solvent is tetrahydrofuran. In certain embodiments, the solvent isdichloroethane. In certain embodiments, the solvent is benzene.

In certain embodiments, the reaction is a reaction below roomtemperature, e.g., a cooled reaction such as a reaction at a temperatureof 0° C. or lower. In certain embodiments, the reaction is a heatedreaction, e.g., a reaction occurring above room temperature. In certainembodiments, the reaction is a reaction run at room temperature. Incertain embodiments, the reaction occurs under an inert atmosphere, e.g,an atmosphere of an inert gas such as nitrogen or argon. In certainembodiments, the reaction takes place under anhydrous conditions, e.g.,conditions that are substantially free of water.

Described herein are compositions comprising a compound describedherein, e.g., a compound of formula (I). In some embodiments, thecompounds described herein are in a composition comprising a solvent,e.g., as a mixture such as a solution or a heterogeneous mixture. Thecomposition can be free of compounds that would react with or degrade acompound described herein e.g., the composition can be substantiallyfree of water and/or substantially free of any reactive gases.

EXAMPLES Example 1 Preparation of Compounds

Polidocanol 41.32 g (70.9 mmol) Polidocanol, 21.07 g (178 4 mmol) ethyllactate, 4.64 g Novozyme 435 and 1.00 g (11 9 mmol) sodium bicarbonatewere added to a 100 mL 1-neck round bottom flask. The flask was thenfitted to a rotary evaporator with the bath temperature set at 62° C.The pressure was slowly reduced to 15 mmHg under moderate rotation andthe reaction mixture was held for 8 hours. Ethyl lactate (5.79 g, 49 0mmol) was added to replenish the amount removed by distillation and themixture was held an additional 16 hours at 62° C. and 15 mmHg The roundbottom flask was removed from the evaporator and the mixture was dilutedwith 20 mL petroleum ether. The solids were separated by vacuumfiltration on a Buchner funnel with a #1 Whatman filter paper. Thefiltered solids were washed with 16 mL petroleum ether and the washliquors were combined with the mother liquors. The combined filtrateswere added to a 100 mL 1-neck round bottom flask and the flask wasaffixed to a rotary evaporator. The petroleum ether and excess ethyllactate were distilled @ 15 mmHg with a bath temperature of 75-80° C.Upon completion of the distillation the pot was cooled and 38.19 g ofPolidocanol lactate was obtained as a lightly colored waxy solid.

What is claimed is:
 1. A composition configured for topical administration, comprising a compound of formula (I):

wherein R¹ is a C₁₂ alkyl; n is an integer from 4 to 10; and R² is hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl; or a pharmaceutically acceptable salt thereof.
 2. The composition of claim 1, wherein R² is alkyl.
 3. The composition of claim 2, wherein R² is C₁₋₄ alkyl.
 4. The composition of claim 1, wherein R² is aryl.
 5. The composition of claim 2, wherein R² is aralkyl.
 6. The composition of claim 1, wherein when R² is not hydrogen, the compound of formula (I) is a racemic mixture of a compound of formula (I).
 7. The composition of claim 1, wherein when R² is not hydrogen, the compound of formula (I) is at least 10% enantiomeric excess of the R stereoisomer.
 8. The composition of claim 7, wherein when R² is not hydrogen, the compounds of formula (I) is at least 50% enantiomeric excess of the R stereoisomer.
 9. The composition of claim 8, wherein when R² is not hydrogen, the compound of formula (I) is at least 75% enantiomeric excess of the R stereoisomer.
 10. The composition of claim 9, wherein when R² is not hydrogen, the compound of formula (I) is at least 85% enantiomeric excess of the R stereoisomer.
 11. The composition of claim 10, wherein when R² is not hydrogen, the compound of formula (I) is at least 90% enantiomeric excess of the R stereoisomer.
 12. The composition of claim 11, wherein when R² is not hydrogen, the compound of formula (I) is at least 95% enantiomeric excess of the R stereoisomer.
 13. The composition of claim 12, wherein when R² is not hydrogen, the compound of formula (I) is least 97% enantiomeric excess of the R stereoisomer.
 14. The composition of claim 13, wherein when R² is not hydrogen, the compound of formula (I) is at least 99% enantiomeric excess of the R stereoisomer.
 15. The composition of claim 1, wherein when R² is not hydrogen, the compound of formula (I) is at least 10% enantiomeric excess of the S stereoisomer.
 16. The composition of claim 1, wherein when R² is not hydrogen, the compound of formula (I) is at least 50% enantiomeric excess of the S stereoisomer.
 17. The composition of claim 16, wherein when R² is not hydrogen, the compound of formula (I) is at least 75% enantiomeric excess of the S stereoisomer.
 18. The composition of claim 17, wherein when R² is not hydrogen, the compound of formula (I) is at least 85% enantiomeric excess of the S stereoisomer.
 19. The composition of claim 18, wherein when R² is not hydrogen, the compound of formula (I) is at least 90% enantiomeric excess of the S stereoisomer.
 20. The composition of claim 19, wherein when R² is not hydrogen, the compound of formula (I) is at least 95% enantiomeric excess of the S stereoisomer.
 21. The composition of claim 20, wherein when R² is not hydrogen, the compound of formula (I) is at least 97% enantiomeric excess of the S stereoisomer.
 22. The composition of claim 21, wherein when R² is not hydrogen, the compound of formula (I) is at least 99% enantiomeric excess of the S stereoisomer.
 23. The composition of claim 1, wherein the compound of formula (I) is represented by the following formula:

wherein n is
 4. 24. The composition of claim 1, wherein the compound of formula (I) is represented by the following formula:

wherein n is
 4. 25. The composition of claim 1, wherein the compound of formula (I) is represented by the following formula:

wherein n is
 4. 26. The composition of claim 1, wherein the composition is a gel.
 27. A composition configured for topical administration, comprising a compound of formula (I):

wherein R¹ is a C₈₋₃₅ alkyl; n is an integer from 4 to 10; and R² is hydrogen, alkyl, aryl, heteroaryl, or heterocyclyl; or a pharmaceutically acceptable salt thereof.
 28. The composition of claim 27, wherein R¹ is a C₈₋₂₅ alkyl group.
 29. The composition of claim 28, wherein R¹ is a C₁₀₋₂₀ alkyl group.
 30. The composition of claim 29, wherein R¹ is a C₁₀₋₁₅ alkyl group.
 31. The composition of claim 30, wherein R¹ is a C₁₂ alkyl group.
 32. The composition of claim 27, wherein R² is alkyl.
 33. The composition of claim 32, wherein R² is C₁₋₄ alkyl.
 34. The composition of claim 27, wherein R² is aryl.
 35. The composition of claim 32, wherein R² is aralkyl.
 36. The composition of claim 27, wherein when R² is not hydrogen, the compound of formula (I) is a racemic mixture of a compound of formula (I).
 37. The composition of claim 27, wherein when R² is not hydrogen, the compound of formula (I) is at least 10% enantiomeric excess of the R stereoisomer.
 38. The composition of claim 27, wherein when R² is not hydrogen, the compounds of formula (I) is at least 50% enantiomeric excess of the R stereoisomer.
 39. The composition of claim 38, wherein when R² is not hydrogen, the compound of formula (I) is at least 75% enantiomeric excess of the R stereoisomer.
 40. The composition of claim 39, wherein when R² is not hydrogen, the compound of formula (I) is at least 85% enantiomeric excess of the R stereoisomer.
 41. The composition of claim 40, wherein when R² is not hydrogen, the compound of formula (I) is at least 90% enantiomeric excess of the R stereoisomer.
 42. The composition of claim 41, wherein when R² is not hydrogen, the compound of formula (I) is at least 95% enantiomeric excess of the R stereoisomer.
 43. The composition of claim 42, wherein when R² is not hydrogen, the compound of formula (I) is least 97% enantiomeric excess of the R stereoisomer.
 44. The composition of claim 43, wherein when R² is not hydrogen, the compound of formula (I) is at least 99% enantiomeric excess of the R stereoisomer.
 45. The composition of claim 27, wherein when R² is not hydrogen, the compound of formula (I) is at least 10% enantiomeric excess of the S stereoisomer.
 46. The composition of claim 27, wherein when R² is not hydrogen, the compound of formula (I) is at least 50% enantiomeric excess of the S stereoisomer.
 47. The composition of claim 46, wherein when R² is not hydrogen, the compound of formula (I) is at least 75% enantiomeric excess of the S stereoisomer.
 48. The composition of claim 47, wherein when R² is not hydrogen, the compound of formula (I) is at least 85% enantiomeric excess of the S stereoisomer.
 49. The composition of claim 48, wherein when R² is not hydrogen, the compound of formula (I) is at least 90% enantiomeric excess of the S stereoisomer.
 50. The composition of claim 49, wherein when R² is not hydrogen, the compound of formula (I) is at least 95% enantiomeric excess of the S stereoisomer.
 51. The composition of claim 50, wherein when R² is not hydrogen, the compound of formula (I) is at least 97% enantiomeric excess of the S stereoisomer.
 52. The composition of claim 51, wherein when R² is not hydrogen, the compound of formula (I) is at least 99% enantiomeric excess of the S stereoisomer.
 53. The composition of claim 27, wherein the compound of formula (I) is represented by the following formula:

wherein n is
 4. 54. The composition of claim 27, wherein the compound of formula (I) is represented by the following formula:

wherein n is
 4. 55. The composition of claim 27, wherein the compound of formula (I) is represented by the following formula:

wherein n is
 4. 56. The composition of claim 27, wherein the composition is a gel. 